This invention relates to novel compositions and methods for inhibiting the activity of mammalian DNA polymerase .alpha., bacterial DNA polymerase III or viral-specific DNA polymerases.
Prior to the present invention, 6-substituted uracils of the formula: ##STR8## wherein Y is hydrogen and X is p-n-butyl are strong inhibitors against polymerase .alpha. but not against B. subtilis DNA polymerase III. In contrast, when X or Y is methyl or chlorine, the uracil is a strong inhibitor of B. subtilis DNA polymerase III, but has no measurable effect on DNA polymerase .alpha.. It is believed that these uracils function by a mechanism that involves the specific pairing of substituents of the uracil moiety with template cytosine and binding of the 6-aryl group and its substituents to the polymerase, thereby sequestering the polymerase in a relatively stable protein: drug template complex.
It would be desirable to provide more potent and/or selective inhibitors of specific polymerases including polymerase .alpha., polymerase III and viral-specific polymerases so that the polymerases in mammalian cells, bacteria and viruses can be specifically inhibited.